Cargando…

Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy

Because of its anabolic effects on muscle, testosterone is being explored as a function-promoting anabolic therapy for functional limitations associated with aging; however, concerns about testosterone’s adverse effects on prostate have inspired efforts to develop strategies that selectively increas...

Descripción completa

Detalles Bibliográficos
Autores principales: Jasuja, Ravi, Costello, James C, Singh, Rajan, Gupta, Vandana, Spina, Catherine S, Toraldo, Gianluca, Jang, Hyeran, Li, Hu, Serra, Carlo, Guo, Wen, Chauhan, Pratibha, Narula, Navjot S, Guarneri, Tyler, Ergun, Ayla, Travison, Thomas G, Collins, James J, Bhasin, Shalender
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331775/
https://www.ncbi.nlm.nih.gov/pubmed/24305501
http://dx.doi.org/10.1111/acel.12174
_version_ 1782357777764581376
author Jasuja, Ravi
Costello, James C
Singh, Rajan
Gupta, Vandana
Spina, Catherine S
Toraldo, Gianluca
Jang, Hyeran
Li, Hu
Serra, Carlo
Guo, Wen
Chauhan, Pratibha
Narula, Navjot S
Guarneri, Tyler
Ergun, Ayla
Travison, Thomas G
Collins, James J
Bhasin, Shalender
author_facet Jasuja, Ravi
Costello, James C
Singh, Rajan
Gupta, Vandana
Spina, Catherine S
Toraldo, Gianluca
Jang, Hyeran
Li, Hu
Serra, Carlo
Guo, Wen
Chauhan, Pratibha
Narula, Navjot S
Guarneri, Tyler
Ergun, Ayla
Travison, Thomas G
Collins, James J
Bhasin, Shalender
author_sort Jasuja, Ravi
collection PubMed
description Because of its anabolic effects on muscle, testosterone is being explored as a function-promoting anabolic therapy for functional limitations associated with aging; however, concerns about testosterone’s adverse effects on prostate have inspired efforts to develop strategies that selectively increase muscle mass while sparing the prostate. Testosterone’s promyogenic effects are mediated through upregulation of follistatin. We show here that the administration of recombinant follistatin (rFst) increased muscle mass in mice, but had no effect on prostate mass. Consistent with the results of rFst administration, follistatin transgenic mice with constitutively elevated follistatin levels displayed greater muscle mass than controls, but had similar prostate weights. To elucidate signaling pathways regulated differentially by testosterone and rFst in prostate and muscle, we performed microarray analysis of mRNAs from prostate and levator ani of castrated male mice treated with vehicle, testosterone, or rFst. Testosterone and rFst shared the regulation of many transcripts in levator ani; however, in prostate, 593 transcripts in several growth-promoting pathways were differentially expressed after testosterone treatment, while rFst showed a negligible effect with only 9 transcripts differentially expressed. Among pathways that were differentially responsive to testosterone in prostate, we identified ornithine decarboxylase (Odc1), an enzyme in polyamine biosynthesis, as a testosterone-responsive gene that is unresponsive to rFst. Accordingly, we administered testosterone with and without α-difluoromethylornithine (DFMO), an Odc1 inhibitor, to castrated mice. DFMO selectively blocked testosterone’s effects on prostate, but did not affect testosterone’s anabolic effects on muscle. Co-administration of testosterone and Odc1 inhibitor presents a novel therapeutic strategy for prostate-sparing anabolic therapy.
format Online
Article
Text
id pubmed-4331775
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher BlackWell Publishing Ltd
record_format MEDLINE/PubMed
spelling pubmed-43317752015-02-19 Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy Jasuja, Ravi Costello, James C Singh, Rajan Gupta, Vandana Spina, Catherine S Toraldo, Gianluca Jang, Hyeran Li, Hu Serra, Carlo Guo, Wen Chauhan, Pratibha Narula, Navjot S Guarneri, Tyler Ergun, Ayla Travison, Thomas G Collins, James J Bhasin, Shalender Aging Cell Original Articles Because of its anabolic effects on muscle, testosterone is being explored as a function-promoting anabolic therapy for functional limitations associated with aging; however, concerns about testosterone’s adverse effects on prostate have inspired efforts to develop strategies that selectively increase muscle mass while sparing the prostate. Testosterone’s promyogenic effects are mediated through upregulation of follistatin. We show here that the administration of recombinant follistatin (rFst) increased muscle mass in mice, but had no effect on prostate mass. Consistent with the results of rFst administration, follistatin transgenic mice with constitutively elevated follistatin levels displayed greater muscle mass than controls, but had similar prostate weights. To elucidate signaling pathways regulated differentially by testosterone and rFst in prostate and muscle, we performed microarray analysis of mRNAs from prostate and levator ani of castrated male mice treated with vehicle, testosterone, or rFst. Testosterone and rFst shared the regulation of many transcripts in levator ani; however, in prostate, 593 transcripts in several growth-promoting pathways were differentially expressed after testosterone treatment, while rFst showed a negligible effect with only 9 transcripts differentially expressed. Among pathways that were differentially responsive to testosterone in prostate, we identified ornithine decarboxylase (Odc1), an enzyme in polyamine biosynthesis, as a testosterone-responsive gene that is unresponsive to rFst. Accordingly, we administered testosterone with and without α-difluoromethylornithine (DFMO), an Odc1 inhibitor, to castrated mice. DFMO selectively blocked testosterone’s effects on prostate, but did not affect testosterone’s anabolic effects on muscle. Co-administration of testosterone and Odc1 inhibitor presents a novel therapeutic strategy for prostate-sparing anabolic therapy. BlackWell Publishing Ltd 2014-04 2013-12-04 /pmc/articles/PMC4331775/ /pubmed/24305501 http://dx.doi.org/10.1111/acel.12174 Text en © 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. http://creativecommons.org/licenses/by/3.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Jasuja, Ravi
Costello, James C
Singh, Rajan
Gupta, Vandana
Spina, Catherine S
Toraldo, Gianluca
Jang, Hyeran
Li, Hu
Serra, Carlo
Guo, Wen
Chauhan, Pratibha
Narula, Navjot S
Guarneri, Tyler
Ergun, Ayla
Travison, Thomas G
Collins, James J
Bhasin, Shalender
Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy
title Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy
title_full Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy
title_fullStr Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy
title_full_unstemmed Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy
title_short Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy
title_sort combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331775/
https://www.ncbi.nlm.nih.gov/pubmed/24305501
http://dx.doi.org/10.1111/acel.12174
work_keys_str_mv AT jasujaravi combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT costellojamesc combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT singhrajan combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT guptavandana combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT spinacatherines combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT toraldogianluca combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT janghyeran combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT lihu combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT serracarlo combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT guowen combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT chauhanpratibha combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT narulanavjots combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT guarnerityler combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT ergunayla combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT travisonthomasg combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT collinsjamesj combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy
AT bhasinshalender combinedadministrationoftestosteroneplusanornithinedecarboxylaseinhibitorasaselectiveprostatesparinganabolictherapy